Programmable ultrasonic field driven microfluidics

ABSTRACT

In one aspect a high frequency ultrasonic microfluidic flow control device is disclosed. The device includes an array of ultrasonic transducers arranged to direct ultrasound to a microfluidic channel. The device further includes one or more driver circuits. Each ultrasonic transducer is associated with one of the one or more driver circuits, and each ultrasonic transducer is driven by a driver signal from the associated driver circuit. The array of ultrasonic transducers and one or more driver circuits are produced in the same semiconductor fabrication process. The device further includes one or more electrical contacts associated with each ultrasonic transducer in the array if ultrasonic transducers, wherein the one or more electrical contacts associated with each ultrasonic transducer applies the driver signal from the associated ultrasonic driver circuit.

CROSS-REFERENCE TO RELATED APPLICATION

This patent document claims priority to and benefits of U.S. ProvisionalAppl. No. 62/911,938, entitled “Valveless Microfluidic Flow ControlUsing Planar Fresnel Type GHZ Ultrasonic Transducers,” filed on Oct. 7,2019. The entire content of the before-mentioned patent application isincorporated by reference as part of the disclosure of this document.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under ECCS-1542081awarded by the National Science Foundation (NSF). The government hascertain rights in the invention.

TECHNICAL FIELD

The technology disclosed in this patent document relates to microfluidicflow control and particle manipulation.

BACKGROUND

The advancement of micro and nanoscale actuators has resulted in manycapabilities to manipulate micro/nano particles and fluidic samples.Efficient microparticle and microfluidic control and manipulation areuseful in many chemical, bio-medical and biological applications. Amongthe contactless manipulation mechanisms, optical and acoustic techniquesare the most common. However, higher forces and the capability toperturb an otherwise laminar flow of fluids without any restrictions ontheir physical properties make acoustofluidics advantageous. Newtechniques and devices are needed for microfluidic flow control.

SUMMARY

Disclosed are new techniques and devices for microfluidic flow controlincluding pumps, mixers, and ultrasonic valves. The disclosed techniquesand devices enable integrated control circuits and microfluidic devicesusing a semiconductor process.

The disclosed subject matter includes a localized microfluidic flowcontrol using a linear array (e.g., 1×4) of Fresnel type gigahertz (GHz)ultrasonic transducers. These devices are fabricated in a planarsemiconductor fabrication process which decouples the fluidics from theelectrical interconnects side of an aluminum nitride based transducerenabling easier integration of GHz transducers and fluidics in adistributed manner. Streaming vortices generated by high frequencyfocused bulk acoustic waves from Fresnel transducers perturb the laminarnature of the microfluidic flow in the channel. By electronicallycontrolling the on and off times of radio frequency (RF) signal inputsto the Fresnel transducers, fluidic steaming can be localized. Changesin the path of polystyrene microbeads in water that were pumped into themicrochannel indicate changes in the fluidic forces acting on them dueto acoustic streaming and change in the flow velocity.

The disclosed subject matter includes acousto-optic modulation at GHzfrequencies in water in a microfluidic channel. The photoelastic effectin water is induced by a silicon based GHz bulk acoustic wave aluminumnitride transducer placed in a Fresnel lens configuration. Planar GHzultrasonic transducers can be fabricated is a complementary metal oxidesemiconductor (CMOS) compatible semiconductor fabrication process withno thin-film release step enabling easier integration with CMOS andmicrofluidics. A UHF vibrometer which is sensitive to changes in therefractive index along the laser path can be used to measure the peaksurface displacement. In an example embodiment, the peak refractiveindex change was determined to be 0(10−6), when 1.08 GHz RF drivevoltages between 1 Vp and 5 Vp were applied to the focusing transducer.Peak phase modulation of 6 mrad was determined from experimental resultsfor 5 Vp RF drive signal. The total modulator area of such a system is0.086 mm². This result provides a framework to implement CMOS integratedacousto-optic modulator arrays.

The disclosed subject matter includes a microfluidic mixer that usesfocused GHz ultrasonic waves to create streaming vortices in anotherwise laminar fluidic flow. Due to high absorption and smallwavelength at gigahertz frequencies, mixing activity is localized.Ultrasonic focusing can be achieved using an aluminum nitride based bulkacoustic wave transducer placed in a Fresnel lens configuration on asilicon substrate. Further, the transducer is on the opposite side offluidics thereby enabling easier integration of transducers and fluidicsin a distributed manner. In an example embodiment, experimental resultsshow microfluidic mixing of blue dye and water had 90% efficiency, whenthe transducer was driven by a 1.06 GHz continuous wave RF signal of 20dBm power.

The disclosed subject matter includes an aluminum nitride based GHzfrequency ultrasonic transducer to realize a microfluidic actuator usingacoustic radiation force and acoustic streaming. The transducer can usefocusing transducers placed in a Fresnel lens configuration, whichgenerates bulk acoustic waves through the silicon substrate adding inphase at the focus. In an example embodiment, peak displacement of 250pm was achieved at the focus with a driving signal at a frequency of1.06 GHz and 5V amplitude input. Acoustic vortices can be formed withmicrofluidic streaming velocity >2.6 mm/s in water droplets placed ontop of the transducer.

In one aspect a high frequency ultrasonic microfluidic flow controldevice is disclosed. The device includes an array of ultrasonictransducers arranged on a first side of a complementary metal oxidesemiconductor (CMOS) substrate, wherein the array of ultrasonictransducers is configured to direct ultrasonic energy into amicrofluidic channel, and wherein the microfluidic channel is structuredon a second side of the CMOS substrate. The device further includes oneor more driver circuits arranged on the first side of the CMOSsubstrate, wherein each ultrasonic transducer is operatively associatedwith one of the one or more driver circuits, wherein each ultrasonictransducer is driven by a driver signal from the associated drivercircuit, and wherein each ultrasonic transducer is configured to produceultrasound in response to an electrical driving signal at a frequencyabove 100 MHz. The device includes one or more electrical contactsassociated with each ultrasonic transducer in the array of ultrasonictransducers, wherein the one or more electrical contacts associated witheach ultrasonic transducer is configured to apply the driver signal fromthe associated driver circuit.

In another aspect, a method of microfluidic flow control is disclosed.The method includes focusing ultrasonic energy, from one or moreultrasonic transducers in an array of ultrasonic transducers, onto amicrofluidic channel, wherein each ultrasonic transducer is configuredto produce ultrasound in response to an electrical driving signal at afrequency above 500 MHz. The method further includes driving each of theone or more ultrasonic transducer in the array of ultrasonic transducersby a different driver circuit to cause a change in microfluidic flow ina channel according to a valve, a pump, or a mixer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts an example of a microfluidic pump including aFresnel-type actuator array and a microfluidic channel on the receiveside of the array.

FIG. 1B depicts an example cross-sectional schematic of the structure ofan aluminum nitride silicon (AlN—Si) stack with images of a Fresnel-zoneplate transmit and circular receive transducers after fabrication.

FIG. 2A depicts a cross-sectional schematic of a structure of an examplelinear array Fresnel type transducer stack with a polydimethylsiloxane(PDMS) microchannel.

FIG. 2B depicts an example image of a fabricated 1×4 Fresnel typetransmit transducer array.

FIGS. 3A-E depict an example process flow used to fabricate and bond amicrofluidic channel, in accordance with some example embodiments.

FIG. 3F depicts an example image of a SU8 mold used to create thechannel.

FIG. 3G depicts an example image of the bonded acoustofluidic device.

FIG. 4 depicts an example block diagram of electronic components used togenerate pulsed RF input signals to drive an acoustofluidic device.

FIG. 5A depicts an example of a scanned surface displacement profile atthe region around a receive transducer.

FIG. 5B depicts an example of a box plot of peak displacement at thefocus for different applied voltages.

FIG. 6 depicts an examples of a pulsed RF signal used for driving anultrasonic transducer.

FIG. 7A shows an example of an RF input to a transducer that is offcausing a negligible change in particle path in the channel.

FIG. 7B shows an RF input to a transducer that is at 50% duty cycle;

FIG. 7C shows an RF input to T1 that is on 10% of the time and input toT2 that is on 90% of the time.

FIG. 7D shows an RF input to T1 that is on 90% of the time and input toT2 that is on 10% of the time.

FIGS. 8A and 8B depict example images of the flow inside 600 μm wide, 27μm high microchannel at different RF pulse repetition frequenciesshowing pronounced change in path lines of the microbeads.

FIG. 9 depicts example image of microfluidic mixer comprising an arrayof Fresnel-type actuators.

FIG. 10 depicts an example of a side view of a two-dimensional array ofFresnel-type actuators with microfluidic channels comprising multipleinput and output ports capable of various functionalities such aslocalized mixing, pumping, and particle trapping.

FIG. 11 depicts an example of a 3×5 array of individually addressableFresnel-transducers.

FIG. 12 depicts an example of a 2D simulation result showing focusing ofsonic waves emanating from a Fresnel type transducer in siliconsubstrate.

FIG. 13 shows an example of a 1D optical and acoustic wave model inwater and PDMS.

FIG. 14 depicts an example of an acoustooptic modulator (AOM)experimental setup.

FIG. 15 depicts examples of peak particle displacement values recordedat the location of the receive transducer using UHF vibrometer.

FIG. 16 depicts an example of a change in refractive index of waterversus applied RF drive voltage.

FIG. 17A depicts an example of a phase difference of the light wavemodulating at GHz frequency.

FIG. 17B depicts a comparison of peak phase difference as a function ofapplied RF voltage obtained from the approximate analysis and from.

FIG. 18A depicts an example of a cross-sectional schematic of thestructure of the AlN—Si stack.

FIG. 18B depicts an example image of a circular transducer on thereceive side after fabrication.

FIG. 18C depicts an example an image of a Fresnel lens transmittransducer after fabrication.

FIG. 19A depicts a sketch showing the location of mixing activity in aPDMS microfluidic channel on top of the AlN—Si transducer stack.

FIG. 19B depicts an example image of a GHz acoustofluidic micro-mixerafter bonding.

FIG. 20A depicts an example of a scanned surface displacement profile atthe region near the receiver for 5V drive voltage.

FIG. 20B depicts an example of a box plot of surface displacement at thepoint of focus with different applied voltages.

FIG. 21A shows an example of an image capture showing negligible mixingactivity near the receive transducer when RF input power is 2 dBm for anexample device.

FIG. 21B shows an example of an image capture showing localized mixingwhen RF input power is 20 dBm for an example device.

FIG. 22A shows an example of a box plot of mixing efficiency fordifferent input power levels with a flow rate of 20 μL/min.

FIG. 22B shows an example of a box plot showing constant mixingefficiency for different flow rates with an input power of 20 dBm.

FIG. 23 shows example plots of a characteristic attenuation length inwater.

FIG. 24 shows an example experimental setup using a vibrometer.

FIG. 25A shows an example of a plot of surface displacement at point offocus vs. input frequency.

FIG. 25B shows an example of scan profile showing surface displacementon a receive side.

FIG. 26 shows an example of a box plot of surface displacement at thepoint of focus with different applied voltages.

FIG. 27A shows an example of a 3D sketch of the microparticle actuatorassembly.

FIG. 27B shows an example of a cross-sectional sketch showing thestreaming vortices in liquid around the receive transducer.

FIG. 27C shows an example of streaming patterns observed around thecircular transducer in the receive side.

FIG. 28 shows an example of a box plot of streaming velocity versusapplied voltage.

DETAILED DESCRIPTION

Section headings are used in the present document only for ease ofunderstanding and do not limit scope of the embodiments to the sectionin which they are described.

Disclosed in this patent document are new techniques and devices formicrofluidic flow control including pumps, mixers, and ultrasonicvalves. The disclosed techniques and devices enable integrated controlcircuits and microfluidic devices using a semiconductor process. Theseintegrated microfluidic and electrical devices are well suited forapplications such as clinical or home-use assays and handheld devicesthat are battery powered to enable ease of use in small clinics or athome. In previous technologies, pumps and valves have take upconsiderable volume and prevent the size, weight, and power ofmicrofluidic assays from being compatible with ease of patient use. Inorder to make assays portable, many previous solutions forgo the use ofpumps and valves, and use passive effects such as surface tension drivenflows to implement assays which prevent more complex microfluidicfunctions such as mixing and valving of reagents. The disclosed in-situdevices provide local sensing and actuation and eliminate the need foroff-chip computing and control elements, further miniaturizing andenhancing the capabilities of the microfluidic system. Computationalelements can be integrated into the devices that, for example, takesensed data, process the sensed based, and learn from past sensingelements to determine the aging of the fluidic system. Thesecomputational elements are implemented in the same semiconductor as themicrofluidic such as a complementary metal oxide semiconductor process(CMOS). In some example embodiments, ultrasonic and acoustic fields arehigh intensity ultrasonic fields that generate high efficacy mixing,pumping, trapping, and sorting of particles. This high intensityultrasound can be generated by summing up the acoustic field from anarray of transducers/actuators driven the integrated CMOS drivercircuits.

INTRODUCTION

Acoustic waves propagating through a medium carry energy and momentum.When these waves propagate from a solid to a liquid medium, energy isdissipated into the liquid due to absorption and diffraction. As aresult, momentum is transferred to the liquid. When the wave in theliquid encounters a particle, scattering and net radiation forces canmove the particle, and the attenuation of the wave causes streaming.

Acoustic streaming is a flow generated by a force arising from thepresence of a gradient in the time-averaged acoustic momentum flux inthe medium. The absorption in the oscillatory field brings about agradient in the flow field. As the absorption coefficient, a increasesnonlinearly with frequency, f. For example, in water, the absorption canbe expressed as α=α₀f². Since the absorption at higher frequenciesoccurs at much smaller distances owing to higher absorption, thegradient of the field into the liquid is higher. Hence, thehigh-frequency sonic waves induce streaming vortices to a greaterextent, compared to low frequency transducers.

High frequency electrical to acoustic transduction is based on surfaceacoustic wave (SAW) or bulk acoustic wave (BAW) technologies. Thesedevices can be fabricated on substrates such as zinc oxide, leadzirconate titanate (PZT), lithium niobate, lithium tantalate andsilicon, and may require higher input voltages for transduction.However, most of these approaches are not CMOS compatible due to theusage of non-CMOS compatible materials such as zinc oxide, PZT, lithiumniobate and lithium tantalate. Furthermore, in these traditional BAW orSAW based acoustofluidic devices, the fluid is placed on the same sideof the substrate as the transducers. Thus, considerable chip area needsto be dedicated to isolate electrical interconnects from the fluidicsamples. All these factors lead to increased device area, expense offabrication, and complexity of electronics required to generate andamplify high voltages at ultra-high frequencies.

In this patent document, disclosed are valveless localized flow controland manipulation using a closely spaced linear array of GHz Fresnel-typefocused ultrasonic transducers. By valveless, we mean that no mechanicaldevices are used as valves. As detailed in this patent document, theultrasonic transducers may act like a valve by preventing flow through achannel. The planar device can be fabricated using CMOS compatiblematerials such as aluminum nitride solidly mounted to silicon substrate.Furthermore, the devices can operate at CMOS compatible RF power and thefluidics are placed on the opposite side of transduction, enablingeasier integration of distributed, yet closely spaced ultrasonictransducers and microfluidics. As an illustrative example, ultrasonictransducers in an array of ultrasonic transducers may be 40μ×40μ or50μ×50μ in size with a gap between ultrasonic transducers of between 2μand 50μ. Other transducer sizes and gaps can also be used.

Material and Methods I

FIG. 1A depicts an example of a microfluidic device 100 including aFresnel-type actuator array and a microfluidic channel on a receive sideof the array, in accordance with some example embodiments. In theexample of FIG. 1A, a microfluidic channel 150 has a fluidic input port110 and fluidic output port 120. The microfluidic channel 150 includessections of channel that may perform different functions such as mixing,pumping, or valving. These functions are performed due to the array ofultrasonic actuators 160 which are each electrically driven by a drivercircuit to cause the array of actuators to perform the function. Forexample, the array of actuators 160 may be driven to cause fluidicsections 140 to cause fluid to be pumped from the input port toward theoutput port. In another example, the array of actuators 160 may bedriven to cause fluidic sections 140 to cause fluid to be mixed in thosesections. In another example, the array of actuators 160 may be drivento cause microfluidic channel 150 to cause a valving function to occursuch that when the array of actuators 160 is electrically driven with aselected electrical signal, microfluidic channel 150 acts as a valve toprevent fluid flow through microfluidic channel 150, and when the arrayof actuators 160 is not electrically driven with the selected electricalsignal, microfluidic channel 150 acts as a valve to allow fluid flowthrough microfluidic channel 150. The fluidic elements 110, 120, 130,140, and 150 can be fabricated on the backside of substrate 170 in acomplementary metal oxide semiconductor fabrication process or anothersemiconductor process such as gallium arsenide (GaAs), silicon germanium(SiGe), or other process. On the frontside of the substrate 170, theultrasonic actuators and driver circuits can be fabricated. In this way,an integrated microfluidic device including fluidic channels, ultrasonicdevices, and driver circuits for the ultrasonic devices can befabricated in a single inexpensive process.

FIG. 1B depicts an example cross-sectional schematic of the structure ofan AlN—Si stack with images of a Fresnel-zone plate transmit andcircular receive transducers after fabrication. The Fresnel zone platetransducers are spaced such that the intensity of the ultrasound at agiven frequency is added in phase to achieve the very high displacementsand velocities needed for nonlinear microfluidic forces to be generated.The electrodes on the transmit side of the silicon substrate can bepatterned in Fresnel zone plate (FZP) configuration in order to focusthe acoustic field emanating through the silicon substrate onto theopposing receive side. The receive electrode can be patterned to form acircular transducer of 2 μm radius. In an example embodiment, theoutermost radius of the Fresnel type transducer was 165 μm. The resonantfrequency of the transducer in this example embodiment was 1.08 GHz. Asthe frequency is increased above 100 MHz, ultrasonic transducers can bemade smaller and placed closer together without the ultrasound producedby the ultrasonic transducers interacting such as by diffraction.

FIG. 2 shows an example of a 1×4 linear array of the Fresnel typetransducers that are spaced 500 μm apart center-center. A PDMSmicrochannel can be bonded such that it encloses the four receivetransducers.

In some example embodiments, a PDMS microfluidic channel has one inletport and an outlet port which may be fabricated using a soft lithographyprocess. The molds for the PDMS channel can made using a photoresist(e.g., SU8 2025) spun onto a clean silicon wafer. The photo resist canbe patterned using UV contact lithography to make a 600 μm wide channel.PDMS may be made by mixing Sylgard 184 silicone elastomer base and acuring agent in the mass ratio 10:1 which can be peeled off from thesilicon wafer and cut to make a microfluidic channel. The PDMS channelcan then be bonded onto the device. An example fabrication process flowis shown in FIGS. 33A-E. For example, a 27 μm thick SU8 mold on Si waferis shown in FIG. 3F. FIG. 3F depicts an example image of a SU8 mold usedto create the channel. The dashed box shows the region of overlapbetween the channel and the receive transducers.

FIG. 4 depicts an example block diagram of electronic of a circuitdesigned to generate pulsed RF input signals to drive acoustofluidicdevices via signals S1-S4. The two outputs from the waveform generatorcan be identical. The signal generator and waveform generator outputscan be synchronized. The signals S1 and S3 can be identical, and thesignals S2 and S4 signals can be identical. For example, pulsed RF inputsignals (S1-S4) to the Fresnel type transmit array can be generatedusing an Agilent N9310A RF signal generator and/or an Agilent 33600Awaveform generator. The output from the RF signal generator can be about20 dBm. Since the RF signal outputs S1-S4 may not be matched to theimpedances of the transducers, the actual RF inputs to each of thetransmit transducers may be <19 dBm.

Experiments and Results I

The Fresnel type transducer can be characterized using a vibrometer(e.g., Polytec UHF-120) prior to bonding the PDMS channel. A continuouswave signal from the vector signal generator can be applied to theFresnel type transmit transducer. With the drive voltage at 5V_(peak),the frequency was varied from 1.01 GHz to 1.1 GHz to determine theresonant frequency. Maximum displacement was observed at 1.08 GHz. Theregion around the small circular receive transducer was then scanned toobserve focusing due to the Fresnel type transmit transducer.

FIG. 5A depicts an example of a scanned surface displacement profile atthe region around a receive transducer for 5V_(peak) RF continuous wave(CW) input. FIG. 5B depicts an example of a box plot of peakdisplacement at the focus for different applied voltages (twenty datapoints are plotted for each voltage). The results show focusing at thelocation of the receive transducer with a beam width ˜10 μm. Peaksurface displacement (u) at the focus was recorded for different RFdrive voltages. A linear behavior of displacement with the appliedcontinuous wave RF input voltage was observed. The average intensity atthe point of focus at the receive side was calculated from

I_(avg)=0.5ρcv²,  EQ. (1)

where, v=μω is the particle velocity of a harmonic system, c is thespeed of sound in the medium, and ρ is the material density. For a drivevoltage of 5 Vp, the average intensity was calculated to be 1.65 kW/cm²on the silicon dioxide surface located on the receive side. However,upon coupling to a liquid, the intensity would decrease asI_(avg liquid)=T I₀e⁻² ^(αx) , where T is the transmission coefficientof the wave in the liquid. The transducer array was then bonded to thePDMS channel as described in the previous section. In some exampleembodiments, ultrasound intensities generated by the ultrasonictransducers of between watts per square centimeter and 1-2 kilowatts persquare centimeter can be sufficient to cause nonlinear effects in thefluid depending on the specific fluid used.

DI water with 2 μm polystyrene beads can be pumped into the microchannelat a constant flow rate of 10 μL/min using a syringe pump. Polystyrenebeads were added to observe the change in the fluidic path due to thegeneration of acoustic streaming in the channel when the acoustictransducers were excited with the pulsed RF signals.

Pulsed RF signals (S1-S4) were applied to the Fresnel type transducerarray, such that the alternate transducers were excited by signals ofthe same phase, repetition frequency and duty cycle. The signals to theother pair of transducers were similar but complements to that of thefirst pair. Generated pulsed RF signals S1 and S2 acquired from anAgilent DSO9404A oscilloscope are shown in FIG. 6, indicating theircomplementary nature. FIG. 6 at the top depicts an example of a pulsedRF signal S1(S3) of 10% duty cycle and S2(S4) of 90% duty cycle, at thebottom a pulsed RF signal S1(S3) of 50% duty cycle and S2(S4) of 50%duty cycle. Pulse repetition frequency may be set to 100 kHz, and RFsignal was 1.08 GHz. Signals are slightly offset in the images toindicate non-overlapping and complementary behavior. The signals were˜5.4 Vpp.

While the continuous wave RF input from the RF signal generator can befixed at 1.08 GHz, the parameters of the pulsed wave output of thewaveform generator can also be varied. In some experiments, the pulserepetition frequency was varied from 100 kHz to 500 kHz, and the signalduty cycle was changed to 10%, 25%, 50%, 75% and 90% keeping therepetition frequency constant at 100 kHz.

The acoustofluidic device was placed under a high-speed microscope(e.g., Keyence VW9000/VH-Z100R) to capture the fluidic flow due toperturbation from the Fresnel-type transducers. Initially, flowconditions were captured when the RF input to the transducers were off.Streamlined flow was observed in the channel. This is because, for amicrochannel of height 27 μm and width 600 μm with flow rate of water 10μL/min, the flow velocity (U) and the Reynolds number (Re) given by (2)are 10.18 mm/s and 0.531 respectively. The symbols: ρ denotes fluiddensity and η is the fluid viscosity

Re=ρUl/η  EQ. (2)

Then, the pulse repetition frequency was set to 100 kHz and the dutycycle was 50%. Changes in the flow were observed in the channel due toacoustic streaming generated by the GHz sonic waves. The duty cycle ofthe pulse was changed keeping the repetition frequency constant at 100kHz. When the on-time of transducers were 10% of the pulse period(t_(on)=1 μs), a negligible change in the fluid flow near thosetransducers was observed. However, changes in the particles' path wereobserved around transducers that were on for 90% of the cycle (ton=9μs). This is because the characteristic time of the 2 μm microbeads isabout 1.5 μs. The characteristic time, (τ_(p)) for Stokes particles in aflow is given by:

τ_(p)=(2a ²ρ_(p))/(9η) EQ. (3)

where, a and ρ_(p) are the radius and density of the particle. FIGS.7A-7D show image captures of the fluid flows around receive transducers1 and 2 of the 1×4 array when the RF input was off, at 50%, 10% and 90%duty cycles. FIGS. 7A-7D depict example images of the flow inside 600 μmwide, 27 μm high microchannel at different RF input conditions. FIG. 7Ashows an RF input to transducers was off negligible change in particlepath in the channel. FIG. 7B shows at 50% duty cycle. FIG. 7C shows anRF input to T1 is on 10% of the time and input to T2 is on 90% of thetime. FIG. 7D shows an RF input to T1 is on 90% of the time and input toT2 is on 10% of the time. Notice negligible change in particle pathlines when transducers (T1 or T2) are on for <τ_(p). Dashed red boxesshow location of streaming activity around transducers T1 and T2 of the1×4 array.

The pulse repetition frequency can be changed to 500 kHz (<τ_(p) of themicrobead) with the duty cycle of the pulse set to 50%. Similar flowconditions as that of the case when the RF signal input was pulsed for10% duty cycle were observed with 100 kHz repetition frequency. However,the path lines of the microbeads around T3 location seemed to be moreperturbed than that at T1 and T2. Comparing this image with that of thecase where RF pulse condition was 50% duty cycle and 100 kHz repetitionfrequency, we can deduce that the flow rate changed as the microbeadstraveled across transducers. Because of the change in flow velocity inthe channel, the drag forces acting on the microparticles would havealso changed. The drag force acting on a spherical particle is given by:

Fd_(rag)=6πηaU  EQ. (4)

The change in fluidic flow rate is due to fluidic streaming generated bythe GHz focused ultrasonic beam. At higher frequencies, attenuation influids play a key role as the attenuation coefficient, α(f)=α₀f², is astrong function of frequency. In pure water, the characteristicattenuation length, α⁻¹, is about 30 μm at 1.08 GHz and 20° C.temperature. Previously we measured streaming velocities of >2.6 mm/sfor 5 Vp continuous wave RF drive voltage. Using these Fresneltransducers, we also showed mixing of blue dye and water. Such a devicecould find use as a micro-pump provided the channel is optimized forfluidic resistance and backpressure.

FIG. 8 depicts example images of the flow inside 600 μm wide, 27 μm highmicrochannel at different RF pulse repetition frequencies showing achange in path lines of the microbeads near transducer T3 indicatingchanges in the drag forces acting on the particles due to streaminginduced change in flow velocity. At (a), for a pulse repetitionfrequency of 100 kHz and 50% duty cycle. At (b) for pulse repetitionfrequency of 500 kHz and 50% duty cycle. The dashed boxes show locationof fluidic activity around transducers T1, T2 and T3 of the 1×4 array.

FIG. 9 depicts example image of microfluidic mixer consisting of anarray of Fresnel-type actuators.

FIG. 10 depicts an example of a two-dimensional array of Fresnel-typeactuators with microfluidic channels consisting of multiple input andoutput ports capable of various functionalities such as localizedmixing, pumping, and particle trapping.

FIG. 11 depicts an example of a 3×5 array of individually addressableFresnel-type transducers (right).

Valveless localized flow control and manipulation of microfluidics usinga closely spaced array of GHz Fresnel-type focused ultrasonictransducers are described in this patent document. In some exampleembodiments, an acoustofluidic transducer is planar and CMOS compatiblemaking it easier to integrate with fluidics and CMOS electricalcircuits.

The high attenuation at GHz frequency and focused ultrasonic beamgenerate strong and localized streaming force in the liquid. Thisperturbation can be used to manipulate microparticles, induce mixing offluids and control the flow of fluids. The mixing and flow control doesnot depend on the electrical properties of the fluid such as theconductivity of the fluid or the dielectric properties of the fluid.

With proper electrical matching of the electrical circuits to theFresnel-type transmit transducers, more efficient streaming activity canbe observed. Further, upon optimizing the channel dimensions forbackpressure, resistance and its placement around the receivetransducers, the transducer array can be used as a valveless acousticmicropump.

Integrated CMOS-acoustofludic devices are enabled by the disclosedfabrication process and the RF input power for transduction, and thefluidic systems being decoupled from the electrical interconnects. Sucha device will reduce the size and cost of the test setting drastically,and can enable digital control and automation of bio-chemical analytesin a closed lab-on-chip environment.

Acousto-Optic Modulation of Water Using Planar Fresnel GHz UltrasonicTransducer

Interaction between light and matter have been used in severalapplications including electrical signal processing, and to studyproperties of various physical, chemical and biological samples.Modulation of light due to such interactions can be achieved usingphotoelastic, electro-optic, thermo-optic and Faraday effects. However,most of these effects are observable only in certain materials, and thecoefficients that relate to the change in the optical parameter understudy with the applied energy, is higher in the case of photoelasticeffect.

The photoelastic or piezo-optic effect is observed when the strain dueto the propagation of sound causes a change in the atomic latticespacing thereby changing the dielectric constant and the refractiveindex of the medium. The photoelastic effect is used in a number ofacousto-optic devices such as modulators, deflectors, variable delaylines, analyzers and tunable optical filters.

Light wave propagating in a medium perturbed by sound waves getsscattered. The interaction is usually categorized into three cases basedon the physical conditions of the light and sound waves. When the widthof the light beam is lesser than the wavelength of the sound waves inthe medium, just bending of light is observed due to the slow variationof the refractive index. When the width of light beam is greater thanthe acoustic wavelength, periodic variation of the index can generatelight beams of different frequencies at different angles. Suchinteraction occurs under Raman-Nath conditions. In the third case, knownas Bragg diffraction, light beam incident at a particular angle ofincidence into a medium perturbed by acoustic waves, reflects off themoving diffraction grating and emerges as a single diffracted lightbeam. These scattering effects are pronounced when the acousticwavelength is comparable to that of the light, allowing the latter twophenomena useful for characterizing properties of solids and liquids,modulating the intensity and phase of light, imaging acoustic fields,correlating signals on optical beams, etc.

Several high frequency acousto-optic modulators have been reported usingsurface acoustic wave (SAW) and bulk acoustic wave (BAW) transducers.However, integration of fluidics with ultra-high frequency (UHF)acoustic transducers for modulation has remained a challenge due to thefollowing reasons. As the attenuation coefficient of liquids increasewith frequency, the extent of observable AOM in them is limited to a fewpm, thus requiring microfluidic technology. Secondly, the liquids mustbe placed on the same side of the transducer, as a result, considerablearea is required to isolate the electrical interconnects of thetransducers from the fluidic sample. Lastly, the sensitivity of theirresonance to mass loading requires feedback control for optimaloperation.

Described below is a CMOS compatible GHz focused bulk acoustic wavetransducer that is used to modulate the refractive index of water, andwater-based solutions contained in a microfluidic reservoir. The planartransducer with electrical input on the opposite side of the focusedbeam output enables easier integration with fluidics for AOM. A UHFlaser vibrometer, which is sensitive to refractive index variationsalong its path is used to determine the change in refractive index ofwater.

Material and Methods II

A planar GHz bulk acoustic wave transducer was used here. The electrodeson the transmit side of the silicon substrate were patterned in Fresnelzone plate (FZP) configuration in order to focus the emanating acousticfield through the silicon substrate onto the opposing receive side. Thereceive electrode was patterned to form a circular transducer of 2 μmradius. The cross-sectional sketch of the simplified GHz transducerstack with images of the fabricated planar FZP shaped AlN transducer onthe transmit side and a small circular AlN transducer on the receiveside are shown in FIG. 1B.

The resonant frequency of the transducer stack was 1.08 GHz. The Fresnellenses can be designed for other frequencies between about 100 MHz to 10GHz. As the frequency decreases, the wavelength of the ultrasonic wavesincreases, making the ring radii and the lens size too large to focusthrough the silicon wafer, and a low density of actuators is possible.At the very high frequency, the wavelength is small, enabling increasednumber of transducers for a given area. However, at the higherfrequencies, the absorption in the silicon and the fluids is higher,reducing the volume of the microfluidic channel that can be effectivelyilluminated by the ultrasonic fields and the associated gradients. TheFresnel zones were designed such that the focal length at the resonantfrequency corresponded to the thickness of the silicon substrate. Fiveelement Fresnel rings were used, and the radius of the outermost ringwas 165 μm. The 2D PZFlex simulation result for normalized acousticpressure showed focusing to be at 725 μm in silicon (see FIG. 12).

A square PDMS microfluidic reservoir of height 27.3 μm and 5 mm widewith a fluidic inlet port was fabricated using soft lithography process.The molds for the PDMS channel can be made using SU8 2025 photoresist.The surfaces of the cured PDMS channel and the AlN/Si transducer stackcan be modified using a room temperature plasma cleaner for 30 s beforebonding. Further, the thickness of PDMS was at least 2 mm.

FIG. 12 depicts a 2D PZFlex simulation result showing focusing of sonicwaves emanating from a Fresnel type transducer in silicon substrate. Theinset is the normalized off-axis pressure profile at the focal point.

FIG. 13 depicts an example of a 1D wave model of a wave propagating from27.3 μm thick water to 2 mm thick PDMS. Inset shows that the acousticwave attenuation in water and PDMS. Also, negligible attenuation of theoptical wave in both the media can be observed.

At high frequencies, the optical and acoustic wavelengths arecomparable, leading to higher scattering. Further, as the absorption inwater as well as in PDMS is high, the acoustic waves get attenuatedrestricting the creation of standing waves in the channel. FIG. 13 showsthe 1D optical and acoustic wave model in water and PDMS.

1D PZ-Flex model of the AlN transducer stack was also simulated,initially with air backing on both the sides, and later with water ofthickness corresponding to that of the microfluidic reservoir on oneside of the stack. An absorbing boundary condition was used in thesimulation to mimic the effect of thick PDMS channel. The simulationresults showed that the shift in resonance due to fluidic loading was ˜3MHz, indicating a negligible (<0.3%) frequency shift.

Experiments and Results II

A continuous wave RF signal from the vector signal generator was appliedto the Fresnel lens type transducer. The resonant frequency of thetransducer was determined. Maximum surface displacement was observedwhen the frequency of the RF input signal was 1.08 GHz. The regionaround the small circular receive transducer was scanned to determinethe surface displacement profile. The surface displacement profilearound the receive transducer is shown in FIG. 5A for 5V_(p), 1.08 GHzRF input signal. The peak displacement ˜250 pm was achieved with <10 μmFWHM confirming focusing of GHz ultrasonic waves.

A PDMS microchannel was then bonded to the transducer such that itcompletely enclosed the receive transducer. The bonded device was thenplaced under a Polytec UHF-120 vibrometer as shown in FIG. 14 formeasurement of optical path length shifts in the water.

FIG. 14 depicts an example of an AOM experimental setup. The laser lightfrom Polytec vibrometer was focused at the receive transducer to measurethe surface displacement with and without water.

Green laser light (λ=532 nm) from the Polytec UHF-120 vibrometer wasfocused at the receive transducer. Peak displacement was measured fordifferent RF input voltages with air in the PDMS cavity. Later, thecavity was filled with DI water. The surface displacement at the samelocation was measured for different RF input voltages. The error barplot of the measured displacements is shown in FIG. 15. Water was thenreplaced with water-based solutions such as saltwater and sugar syrup,and the displacement at the receiver was measured. This was done toverify the correctness of the range of displacement readings displayedby the vibrometer software, also to see slight distinction in thedisplacement values for solutions of different acousto-optic properties.

Laser doppler vibrometer (LDV), generally used to measure vibrations isbased on Mach-Zehnder interferometer. The system is sensitive to changesin the refractive index (Δn) along the path of the laser beam. Theoptical path length (OPL) measured by the LDV is given by

OPL=∫_(δ) ₀ _(cos(ωt)) ^(z) ^(H) n(z,t)dz  EQ. (5)

where, δ₀ cos (ωt) is the displacement observed at the receiver withoutwater changing at acoustic frequency

$\left( {f = \frac{\omega}{2\pi}} \right),$

and z_(H) is the height of the microfluidic channel. Suppose theparticle displacement in water decays as δ(z,t)=δ₀e^(−αz)Cos(k_(ac)z−ωt), with α being the attenuation coefficient, and k_(ac)the propagation constant of the acoustic wave. The first order strain inwater is then,

ϵ(z,t)=δ₀ e ^(−az) cos(ωt)[α cos(k _(ac) z)+k _(ac) sin(k _(ac) z)]  EQ.(6)

The peak change in refractive index, Δn_(p)∝ϵ_(max), is given byΔn_(p)≈−0.5 n³p ϵ_(max), where p is the photoelastic constant.

FIG. 15 depicts examples of peak particle displacement values recordedat the location of the receive transducer using UHF vibrometer.

The modulating refractive index in the medium is then,

n(z,t)=n ₀ −pn ₀ ³δ₀ e ^(−αz) cos(ωt)[α cos(k _(ac) z)+k _(ac) sin(k_(ac) z)]  EQ. (7)

Substituting (7) in (4) gives,

OPL=∫_(δ) ₀ _(cos(ωt)) ^(z) ^(H) (n ₀ −pn ₀ ³δ₀ e ^(−αz) cos(ωt)[α cos(k_(ac) z)+k _(ac) sin(k _(ac) z)]  EQ. (8)

Upon solving and simplifying the definite integral, we get

OPL=n ₀[z _(H)=δ₀ cos(ωt)]+pn ₀ ³δ₀ cos(ωt)[e ^(−αδ) ⁰ ^(cos(ωt))cos(δ₀k _(ac) cos(ωt)−e ^(−αz) ^(H) cos(k _(ac) z _(H))]EQ. (9)

An alternate equation, less rigorous mathematically, may be derived todetermine the approximate change in refractive index assuming negligibleeffects encountered by the acoustic wave propagating from solid to theliquid medium. As the particle velocity measured by the LDV(v_(LDV)) isthe time rate of change of OPL,

$\begin{matrix}{v_{LDV} = {\frac{{du}_{LDV}}{dt} = {\frac{d({OPL})}{dt} \approx {\frac{d}{dt}\left( {n*z} \right)}}}} & {{EQ}.\mspace{14mu} (10)}\end{matrix}$

where, z is the height of the cavity containing the liquid undergoingmodulation. If Δz and Δn are the changes in cavity height and theliquid's refractive index, such that Δz«z₀ and Δn«n₀ respectively, thenz and n may be written as EQ. (11). The terms with a subscript ‘0’indicate initial values

z=z ₀ =Δze ^(−jωt) ,n=n ₀ −Δne ^(−jωt)  EQ. (11)

Since the excitation signal is harmonic, upon substituting equations(11) in (10), we getjωu_(LDV)e^(jωt)=n·(−Δz·j·ω·e^(jωt))+z(−Δn·j·ω·e^(jωt)). The change inrefractive index is

$\begin{matrix}{{\Delta \; n} = {\frac{{nu}_{actual} - u_{LDV}}{z} \approx \frac{{n_{0}u_{actual}} - u_{LDV}}{z_{0}}}} & {{EQ}.\mspace{14mu} (12)}\end{matrix}$

The change in refractive index for water was also determined usingequation (12) from the measured displacement values (FIG. 15) and bycalculating n₀ of water for λ₀=532 nm at 20° C. The values were comparedto the theoretical value of Δn_(p), with p=0.31 for water. FIG. 16 showsthe value of Δn for different RF drive voltages. The relationshipbetween Δn and V is linear and the Δn_(p) is of the 0(10⁻⁶).

The non-linearities in the water due to acoustofluidic effects, and thetemperature changes due to the incident optical wave and focusedultrasonic wave at the receive transducer also affect the refractiveindex. The changes in temperature due to green laser of 5mW power anddue to ultrasound were calculated to be ˜0.5 mK (for 30 minute exposure)and 5 mK (5 V_(p) RF input) respectively. Corresponding Δn is of theorder of 10⁻⁸ and 10⁻⁷ respectively, indicating that the modulation ismostly due to photoelastic effect.

FIG. 16 depicts an example of a change in refractive index of waterversus applied RF drive voltage.

The change in the phase (Δϕ) due to the refractive index modulation wascalculated from EQ. (9) and compared with that from EQ. (12). FIG. 17shows the phase difference modulating at 1.08 GHz acoustic frequencydetermined using EQ. (9) and (13). From the OPL approach EQ. (13), thepeak value of Δϕ was determined to be 6 mrad when the input to theFresnel transducer was 5 Vp RF signal.

$\begin{matrix}{{\Delta \; \varphi} = {{\frac{2\; \pi}{\lambda_{0}}\left( {n_{0}*2\; z_{H}} \right)} - {\frac{2\; \pi}{\lambda_{0}}\left( {n*2*{OPL}} \right)}}} & {{EQ}.\mspace{14mu} (13)}\end{matrix}$

A GHz frequency strain wave in the fluid can lead to change in the indexof refraction in the liquid owing to photoelastic effect. The focusedbeam of very high intensity, 1.7 kW/cm², emanating from the Fresnel typetransducer is used to modulate the optical parameters of materials, suchas the optical index of refraction. The decaying ultrasonic waves in theliquid modulates its refractive index and provides a net phase shift tothe optical beam incident and reflected off the top metal electrode ofthe receive transducer. The calculated change in the refractive index ofwater is on the 0(10⁻⁶). The phase of the optical beam is modulated atacoustic frequency of 1.08 GHz, and a peak phase difference of 6 mradwas achieved when the Fresnel type transmit transducer was driven by a 5V_(p) RF signal. Further, the total modulator area of such a system is0.086 mm². With a proven approach for monolithic integration of AlNtransducers with CMOS circuits, this device is a pathway towardsinexpensive CMOS integrated acousto-optic modulator arrays with acapability of digital and analog feedback control of phase and arrayhomogeneity.

FIG. 17A depicts an example of a phase difference of the light wavemodulating at GHz frequency. FIG. 17B depicts a comparison of peak phasedifference as a function of applied RF voltage obtained from theapproximate analysis and from.

Localized Microfluidic Mixer Using Fresnel Ghz Ultrasonic Transducer

Efficient and rapid mixing of laminar fluid flows is critical forseveral microfluidic applications such as drug screening, medicaldiagnosis, chemical synthesis, genetic analysis, protein foldingstudies, etc. Traditional macroscopic fluidic mixing strategiesemploying long channels, mechanical or magnetic stirring elements becomeimpractical for microscale mixing. Furthermore, as microfluidic flowlies in the laminar regime, mixing is dominated by diffusion, which isslow and prevents mixing in channel lengths compatible with microfluidicchip dimensions.

To improve the mixing time and the homogeneity of mixing (i.e., mixingefficiency), various approaches have been employed. These approaches canbe classified into passive and active mixing based on the absence orpresence of an external energy source. While passive mixing is usuallyimplemented by channel geometries that fold flow lines, the externalenergy in active mixers is used to trigger localized motion of thefluids. Active mixers generally outperform the passive counterparts withrespect to mixing time, efficiency, and required channel length.

Active microfluidic mixers employing external electrical, thermal,magnetic or acoustic energy sources have been reported. However,acoustic and ultrasonic based mixers are advantageous as they performcontactless fluidic mixing without depending on the electricalproperties of the fluid such as the conductivity of the fluid or thedielectric properties of the fluid.

Acoustic mixers perturb the streamlined flow in the microfluidic channelby employing bulk acoustic wave (BAW), surface acoustic wave (SAW) ormembrane transducers. Many acoustic mixers use acoustic bubbles toefficiently generate vortices to rapidly mix fluids. However, owing totheir complicated constructions and instability of the bubblegeneration, direct generation of streaming without the assistance ofbubbles is preferred.

For efficient and rapid mixing, strong acoustic streaming forces arerequired. The body force, F_(B), that generates streaming vortices atthe edges of the acoustic fields in fluids is given by F_(B)=ραv². Here,the attenuation coefficient in the fluid α, and the particle velocity vscale as f² and f respectively; f being the frequency of the acousticwave. Thus, as F_(B)∝f⁴, much interest is being showed in developingultra-high frequency SAW and BAW based microfluidic mixers. However,most of these actuators reported thus far require >10V drive voltage andare fabricated using non-CMOS compatible materials such as zinc oxide,lithium niobate, lithium tantalate or lead zirconate titanate (PZT).Furthermore, in most of these devices, the fluid is placed on the sameside of these transducers. This then forces considerable chip areadedicated to isolate electrical interconnects from the fluidic sample.These factors can result in increased device area, expense offabrication, and electronics complexity in the generation andamplification of high voltages at ultra-high frequencies.

Described above is an acoustofluidic micro-mixer that uses GHz focusedultrasonic beam to create localized streaming vortices in themicrochannel. The device is fabricated without any thin-film releasesteps, using CMOS compatible materials like aluminum nitride (AlN)solidly mounted to silicon substrate. Further, the placement of thetransducers on the opposite side of fluidics enable easier integrationof distributed CMOS electronics with AlN transducers on one side, andthe fluidic system on the opposite side. The ability to beam form fromGHz sonics is further enabled by the thickness of the silicon wafer asbeing many wavelengths thick, enabling Fraunhofer and Fresneldiffraction analysis to be used.

FIG. 18A depicts an example of a cross sectional schematic of thestructure of the AlN—Si stack. FIG. 18B depicts an example image of thecircular transducer on the receive side after fabrication. FIG. 18Cdepicts an example an image of the Fresnel lens transmit transducerafter fabrication.

Material and Methods III

Planar AlN based transducer stack for GHz ultrasonics, similar to theone previously reported by our group, was used here. The AlN transducerswere fabricated at the Institute of Microelectronics (IME) in Singaporeunder the IARPA—Trusted Integrated Chips (TIC) program. Resonantfrequency of the transducer was 1.06 GHz. The transducer consisted of200 nm molybdenum as electrode layers, 2 μm thin film piezoelectric AlN,and 1.3 μm thick insulating silicon dioxide layer, on a 725 μm thicksilicon wafer.

The electrodes on one (transmit) side of the silicon substrate werepatterned in Fresnel zone plate (FZP) configuration in order to focusthe emanating acoustic field through the silicon substrate onto theopposing receive side. The receive electrodes were patterned to form acircular transducer of 2 μm radius. The cross-sectional sketch of thesimplified GHz transducer stack with planar FZP shaped AlN transducer onthe transmit side and a small circular AlN transducer on the receiveside is shown in FIG. 18. AlN in the regions without transduction arenot shown here for simplicity.

In a Fresnel lens design, the distance from each annular zone to thepoint of focus is an integral multiple of the wavelength. As a result,the acoustic waves reach the focal point in phase, interferingconstructively. If the wavelength of the wave in the medium is λ_(Si),the focal length is F, then the radius of each annular zone is given by:

$\begin{matrix}{r_{n} = \sqrt{\frac{n\; \lambda_{Si}}{2}\left( {F + \frac{n\; \lambda_{Si}}{8}} \right)}} & {{EQ}.\mspace{14mu} (14)}\end{matrix}$

The longitudinal speed of sound in silicon being 8000 m/s, the AlNFresnel lens radii were optimized to achieve a focal length of ˜725 μmin silicon for 1.06 GHz using PZFlex simulation software. Five Fresnelrings were used, and the radius of the outermost ring was 165 μm. The 2DPZFlex simulation result for normalized acoustic pressure showedfocusing to be at 725 μm in silicon (see FIG. 12).

FIG. 12 depicts an example of a 2D PZFlex simulation result showing thefocal length of the FZP transducer to be 725 μm in silicon substrate.The inset is the normalized off-axis pressure profile at the focalpoint.

FIG. 19A depicts a sketch showing the location of mixing activity in thePDMS microfluidic channel on top of the AlN—Si transducer stack. FIG.19B depicts an example image of a GHz acoustofluidic micro-mixer afterbonding.

A polydimethylsiloxane (PDMS) microfluidic channel with two inlet portsand an outlet port was fabricated using standard soft lithographyprocess. The molds for the PDMS channel were made using 325 μm thick SU8100 photoresist spun onto a clean silicon wafer. The photo resist waspatterned using UV contact lithography to make a 700 μm wide channel.PDMS resulting by mixing Sylgard 184 silicone elastomer base and curingagent in the mass ratio 10:1 was poured onto the silicon wafer with SU8master. The cured PDMS stamp was then peeled off from the silicon waferand cut to make a microfluidic channel. The surfaces of the PDMS channeland the AlN—Si transducer stack were modified using a room temperatureplasma cleaner for 30 s before bonding. The image of the PDMS channelbonded onto the AlN—Si transducer substrate is shown in FIG. 19A.

Experiments and Results III

The Fresnel type transducer was first characterized using a PolytecUHF-120 vibrometer, before bonding the microfluidic channel. Acontinuous wave signal from a vector signal generator was applied to theFresnel lens type transducer. With the drive voltage amplitude at 5V,the frequency was varied from 1.01 GHz to 1.1 GHz to determine theresonant frequency. The peak displacement was observed at 1.06 GHz. Thesurface displacement near the small circular receive transducer was thenscanned and a narrow beam width ˜10 μm was observed due to focusing ofGHz ultrasonic waves (FIG. 20A). Both these experiments confirmedfocusing of the acoustic wave emanating from the surface of the planarFresnel lens transmit transducer and closely match the results fromPZFlex simulations.

FIG. 20A depicts an example of a scanned surface displacement profile atthe region near the receiver for 5V drive voltage. FIG. 20B depicts anexample of a box plot of surface displacement at the point of focus withdifferent applied voltages (twenty data points are plotted for eachvoltage).

The surface displacement (u) at the center of the receive transducer wasthen recorded as a function of the RF drive voltage. The expected linearbehavior of displacement with applied voltage was observed (FIG. 40.b).From the displacement data, the average acoustic intensity wasdetermined using

I _(avg)=½pv  EQ. (15)

where, p=ρcv is the acoustic pressure, and v=uω is the particle velocityof a harmonic system. For a drive voltage of 5V, the average intensitywas calculated to be 1.7 kW/cm² on the silicon dioxide surface locatedon the receive side. Thus, a very high intensity ultrasonic beam wasrealized from the GHz Fresnel type transducer. After the surfacedisplacement characterization, the wire bond to the printed circuitboard (PCB) were removed and the transducer was cleaned to facilitatebonding of the PDMS microchannel onto the AlN/Si transducer.

The transmit Fresnel transducer located on the bottom side of the bondedmicrofluidic device was again wire bonded to the PCB. The transducer waspowered using an Agilent N9310A signal generator with the inputfrequency fixed at 1.06 GHz, corresponding to the resonant frequency ofthe transducer. Blue colored food dye diluted with water, and water with2 μm polystyrene microbeads were pumped into the microfluidic channel.Polystyrene microbeads were added to enhance the color contrast whilecapturing the mixing activity. The flow rates were controlled usingCorSolutions microfluidic pumps.

Firstly, the RF power from the signal generator was varied from 2 dBm to20 dBm, keeping the flow rates of both the fluids constant at 20 μL/min.Then, the RF power was fixed at 20 dBm and the flow rates were variedfrom 5 μL/min to 20 μL/min. The videos of the mixing of water containingpolystyrene microbeads with diluted blue dye were recorded using adigital handheld camera in both the cases. Five images at differenttimes were captured from the recorded videos, and the mixing efficiencywas calculated using MATLAB. If I_(i) and Ī are the intensity values ofthe i^(th) pixel and the average value of the N pixels in the mixedregion of interest (ROI) respectively, and I_(i)′ and Ī′ are those atthe unmixed region, mixing efficiency is given by:

$\begin{matrix}{{{Mixing}\mspace{14mu} {Efficiency}} = {\left( {1 - \frac{\sqrt{\frac{1}{N}{\sum\limits_{i = 1}^{N}\left( {I_{i} - \overset{\_}{I}} \right)^{2}}}}{\sqrt{\frac{1}{N}{\sum\limits_{i = 1}^{N}\left( {I_{i}^{\prime} - \overset{\_}{I^{\prime}}} \right)^{2}}}}} \right) \times 100}} & {{EQ}.\mspace{14mu} (16)}\end{matrix}$

The box plots of the mixing efficiency for both the experiments areshown in FIG. 22A/B. Intensity values of fifteen pixels from each of thefive images were considered near the mixed and unmixed regions forcalculations. It can be observed that 90% mixing efficiency was achievedwith 20 dBm input power.

The high mixing efficiency means that the mixing is uniform in theregion of interest, near the receive transducer. From FIG. 21 A-B, itcan be observed that the mixing activity is highly localized to <200 μmregion along the width of the channel.

The higher mixing efficiency and localized mixing are due to the GHzfrequency focused ultrasonic beam. At high frequencies, attenuation influids play a key role as the attenuation coefficient, α(f)=α₀f², is astrong function of frequency. In pure water, the characteristicattenuation length, α⁻¹, is about 17 μm at 1.06 GHz at 20° C. From theexperimental surface displacement data, the acoustic intensity of water,I=I₀e^(−α(f)x), is calculated to be 630 W/cm² at the characteristiclength. As a result, the body force,

$F_{B} = \frac{2I\; \alpha}{c}$

is enhanced resulting in localized streaming vortices. Previously, wemeasured the streaming velocities to be >2.6 mm/s for 5V amplitudeinput.

The Reynolds number (Re), that characterizes the importance of inertialand viscous forces is calculated to be <1 for the microfluidicconditions used here, implying the dominance of viscous forces andlaminar flow of fluids. The Reynolds number is calculated using (13),where ρ is the density of the fluid, U is the flow velocity and l is thecharacteristic length of the channel.

$\begin{matrix}{{Re} = \frac{\rho \; {Ul}}{\eta}} & {{EQ}.\mspace{14mu} (17)}\end{matrix}$

Another important dimensionless number, Peclet number (Pe), that is usedto characterize the importance of diffusion to convection in the mixeris calculated to be in the range of about 81-325. Pe is calculated from(14), where D is the diffusivity of the fluid (D=2×10⁻⁹ m²/s). Table 1lists the values of Re and Pe for different flow rates in the channel.

$\begin{matrix}{{Pe} = \frac{Ul}{D}} & {{EQ}.\mspace{14mu} (18)}\end{matrix}$

TABLE I Values of Fluidic Parameters Channel dimensions: W = 700 μm, H =325 μm Flow rate (μL/min) Velocity (mm/s) Re Pe 5 0.37 0.16 81 10 0.730.33 162.5 15 1.1 0.49 244 20 1.46 0.65 325

Described above is a highly localized GHz ultrasonic microfluidic mixerhas been presented. The acoustofluidic mixing device consists of a PDMSmicrofluidic channel bonded to the backside of a silicon chip consistingof a planar AlN—Si transducer stack. The transducer stack consists of anAlN based Fresnel transducer that is used to focus GHz sonic wavesthrough the bulk silicon substrate. The FZP transducer is designed suchthat the focal length is equal to the thickness of the substrate.Further decrease in input voltage needed to achieve fluidic mixing canbe realized by proper matching to the transducer RF impedance.

FIG. 21A shows an example of an image capture showing negligible mixingactivity near the receive transducer when RF input power is 2 dBm FIG.21B shows an example of an image capture showing localized mixing whenRF input power is 20 dBm (LOI: Line of interest; ROI: region of interestfor mixing efficiency calculation).

FIG. 22A shows an example of a box plot of mixing efficiency fordifferent input power levels when flow rate was 20 μL/min. FIG. 22Bshows an example of a box plot showing constant mixing efficiency fordifferent flow rates when input power is 20 dBm. (Frequency of operationis 1.06 GHz; data from five images were used in the calculation.)

Owing to the high dissipation of GHz sonic waves in fluids, a strongstreaming force is generated. This perturbation induces mixing of thetwo fluids—water with polystyrene microbeads and blue dye near thevicinity of the receive transducer. The ability to change the frequencyof ultrasound and the amplitude can also be used to spread the spatialextent of the acoustic force in fluids.

Since the RF voltages required for actuation and the fabrication processare both CMOS compatible, and the fluidic systems are decoupled from theelectrical interconnects, an integrated CMOS-acoustofluidic device canbe realized. Such a device would not only reduce the size and cost ofthe test setting drastically, but also can enable digital control andautomation of bio-chemical analytes in a closed lab-on-chip environment.

CMOS Compatible GHz Ultrasonic Fresnel Microfluidic Actuator

Micro-particle manipulation in liquid is useful in many chemical,biomedical, and biological applications. Among the contactlessmanipulation mechanisms, optical and acoustic techniques are the mostcommon. The laser based optical technique can produce a few pico-Newtonsof trapping forces but cannot control larger biological objects andoperate in a medium of high optical opacity. On the other hand, acousticdevices can be more easily integrated with the microfluidic channel andhave been shown to handle biological particles better because of longerwavelengths and higher radiation forces.

An acoustic wave propagating through a medium carries energy andmomentum. Wave energy is dissipated into the liquid due to absorptionand diffraction, and leads to momentum transfer to the liquid. When thewave encounters an object, scattering and net radiation forces can movethe object. These forces can result in particle trapping, streaming, andatomization. As the acoustic radiation and streaming forces increaseinversely with the acoustic wavelength in the medium, recent works haveincreasingly utilized higher frequencies for microparticle actuation.The gradient force, resulting from the radiation force can further beenhanced by having a larger intensity difference between the center ofthe beam and the peripheral region.

Acoustic beam-based manipulators such as acoustic tweezers that use highfrequency focused ultrasonic beams have recently been explored. Most ofthe high frequency ultrasonic beam manipulators reported so far usesurface acoustic wave (SAW) transducers on non-CMOS compatiblesubstrates such as lithium niobate, lithium tantalate or lead zirconatetitanate (PZT). Further, their actuation requires >10V drive voltage.

Micro-particle actuators based on bulk acoustic wave (BAW) have alsobeen reported for driving circulatory motion in microfluidic chambersand micro droplet ejection. These millimeter scale devices have used PZTtransducers, operate below 200 MHz frequencies, and typically require adrive voltage of a few 10 s-100 s of volts.

Despite the advantages of using high frequency focused ultrasonic beamsfor manipulation of fluid-laden particles, several challenges in theimplementation prevents easy adoption. The expense of fabrication, andgeneration and amplification of high voltages at these frequencies aretwo reasons often mentioned. Another technological impediment is thatconsiderable chip area is required to isolate the electricalinterconnects of the transducers from the fluidic sample; as the fluidis placed on the same surface as the transducer.

Described above is a microscale GHz focused-beam bulk acoustic wavemicroparticle manipulator which decouples the fluidic side from theactuator side. The device is fabricated without any thin-film releasesteps, using CMOS compatible materials such as aluminum nitride (AlN)solidly mounted to silicon substrate. Microfluidic streaming action wasobserved near the vicinity of the focus and the streaming velocity inwater with 2 μm diameter polystyrene microspheres was measured to beabout 2.6 mm/s for a 5V amplitude, 1.06 GHz frequency continuous wave(CW) input.

Fresnel Microfluidic Actuator

Planar AlN based transducer stack for GHz ultrasonics, similar to theone previously reported by our group, was used here. The AlN transducerswere fabricated at the Institute of Microelectronics (IME) in Singaporeunder the IARPA—Trusted Integrated Chips (TIC) program. Resonantfrequency of the transducer was 1.06 GHz. The transducer consisted of200 nm molybdenum as electrode layers, 2 μm thin film piezoelectric AlN,and 1.3 μm thick insulating silicon dioxide layer, on a 725 μm thicksilicon wafer.

The electrodes on one (transmit) side of the silicon substrate werepatterned in Fresnel zone plate (FZP) configuration in order to focusthe emanating acoustic field through the substrate onto the opposingreceive side. The receive electrodes were patterned to form a circulartransducer of 2 μm radius. FIG. 18A shows an example of across-sectional sketch of the simplified GHz transducer stack withplanar FZP shaped AlN transducer on the transmit side and a smallcircular AlN transducer on the receive side. AlN in the regions withouttransduction are not shown here for simplicity.

In a Fresnel lens design, the distance from each annular zone to thepoint of focus is an integral multiple of the wavelength. As a result,the acoustic waves reach the focal point in phase, interferingconstructively. If the wavelength of the wave in the medium is λ_(Si),the focal length is F, then the radius of each annular zone is given by:

$\begin{matrix}{r_{n} = \sqrt{\frac{n\lambda_{Si}}{2}\left( {F + \frac{n\lambda_{Si}}{8}} \right)}} & {{EQ}.\mspace{14mu} (19)}\end{matrix}$

The longitudinal speed of sound in silicon being c_(Si)=7963 m/s, theAlN Fresnel lens radii were optimized to achieve a focal length of ˜725μm in silicon for 1.06 GHz using PZFlex simulation software. FiveFresnel rings were used, and the radius of the outermost ring was 165μm. The 2D PZFlex simulation result for normalized acoustic pressure insilicon showed a maximum pressure around 725 μm (see FIG. 12).

Acoustic Streaming in Fluids

Propagation of an acoustic wave results in acoustic radiation forces onparticles and acoustic streaming of fluids. These are second ordereffects that are caused by nonlinearities in governing physics. When theparticle size is very small compared to the acoustic wavelength of theincident wave, i.e., ka«1 where, k is the propagation constant in thefluid and ‘a’ is the radius of the particle, the acoustic force on theparticle is determined by the spatial gradient of the force potentialfield U, with the particle movement from the region of high forcepotential to low force potential. The acoustic radiation force is givenby:

F _(R) =−∇U  EQ. (20)

and the force potential field is

$\begin{matrix}{U = {\frac{4\pi}{3}{a^{3}\left\lbrack {{f_{1}\frac{1}{2}\kappa_{0}{\langle\left| p_{l} \right|^{2}\rangle}} - {f_{2}\frac{3}{4}\rho_{0}{\langle\left| v_{l} \right|^{2}\rangle}}} \right\rbrack}}} & {{EQ}.\mspace{14mu} (21)} \\{f_{1} = {{1 - {\frac{\kappa_{p}}{\kappa_{l}}\mspace{14mu} {and}\mspace{14mu} f_{2}}} = \frac{2\left( {\frac{\rho_{p}}{\rho_{l}} - 1} \right)}{\frac{2\rho_{p}}{\rho_{l}} + 1}}} & {{EQ}.\mspace{14mu} (22)} \\{\kappa = \frac{1}{\rho c^{2}}} & {{EQ}.\mspace{14mu} (23)}\end{matrix}$

In the above equations, f_(1,2) parameters represent the monopole anddipole scattering coefficients,

|p_(l)|²

is the mean squared pressure,

|v_(l)|²

is the mean squared particle velocity in the fluid, ρ is the density andκ is the compressibility. The subscripts l denote the fluid and p denotethe particle in the fluid medium.

In the Rayleigh regime, where ka«1, scattering force due to thereflection of propagating waves from the particle is small and is oftenneglected. Whereas, in Mie scattering regime, where the particle size iscomparable or larger than the acoustic wavelength, i.e., ka>1,scattering becomes important. The force acting on the particle is now:

−F=

∫ _(S) p ₂ ndS

+

∫ _(S)ρ_(l)(n19 v _(l))v _(l) dS

  EQ. (24)

The integration is over an arbitrary surface, S that encloses theparticle, and {right arrow over (n)} is the vector normal to thesurface. The second order pressure p_(2l) for an inviscid fluid can beobtained from first order terms

p _(2l)=½κ₀

|p _(l)|²

−½ρ₀

|v _(l)|²

  EQ. (25)

As the force potential is proportional to the cube of the particleradius, i.e., F∝a³, larger particles are displaced further away from thecenter of the ultrasonic beam compared to smaller particles. Further, asthe force gradient scales inversely with the acoustic wavelength, highfrequency ultrasonic waves increase both radiation and streaming forces.It is observed that with increasing frequency, the radiation forceincreases much faster than the force due to streaming.

At higher frequencies, attenuation in fluids also play a key role as theattenuation coefficient, α(f)=α₀f², is a strong function of frequency.In pure water, the characteristic attenuation length, α⁻¹ is below 100μm for frequencies above 500 MHz at room temperature (FIG. 23). Thisindicates that the force fields can be highly localized at GHzfrequencies. This can be used in applications such as particle and cellseparation, concentration, droplet production, encapsulation, activesorting, controlled heating, nanotube alignment, viscosity measurement,and aerosol production.

In harmonic systems, the particle velocity in fluid, v_(l), is given byv=ωu_(l), where ω is the angular frequency of the acoustic wave andu_(l) is the displacement of the fluid due to the propagation of theultrasonic wave. For fluids with low Mach

${M = {\frac{v_{l}}{c}1}},$

where c is the acoustic velocity in the fluid, the second orderstreaming velocity is related to the first order velocity in fluid byv_(2s)∝v_(l) ². As the displacement u_(l), is proportional to theapplied voltage, it can be inferred that the second order streamingvelocity increases as the square of the applied voltage, i.e.,v_(2s)∝V_(in) ².

FIG. 23 shows example plots of a characteristic attenuation length inwater.

FIG. 24 shows an example experimental setup using a vibrometer (e.g.,Polytec UHF-120).

Experiments and Results IV

The GHz FZP actuator displacement profile was characterized using aPolytec UHF-120 vibrometer (FIG. 24). Continuous wave (CW) signal fromthe vector signal generator (VSG) was applied to the Fresnel lens typetransducer. Keeping the amplitude at 5V, frequency of the VSG was variedfrom 1.01 GHz to 1.1 GHz to determine the resonant frequency of thedevice. FIG. 25A shows an example plot of surface displacement on thereceive side of the device under test (DUT) for various frequencies.Peak displacement profile was observed at 1.06 GHz, which closelymatches with the PZFlex simulation. FIG. 25B shows the surfacedisplacement profile of the DUT with peak displacement occurring at thelocation of the circular receive transducer. These two results confirmfocusing of the acoustic wave emanating from the planar Fresnel lenstransmit transducer.

The peak surface displacements at the center of the receive transduceras a function of applied voltages for a CW signal of 1.06 GHz is shownin FIG. 26. The expected linear behavior of the displacement withapplied voltage is observed.

From the displacement data for 5V amplitude input, the average acousticintensity I_(avg),

I _(avg)=½pv _(l),  EQ. (26)

with ultrasonic pressure p=ρcv, was calculated to be 1.7 KW/cm² on thesilicon dioxide surface located on the receive side. Thus, a very highintensity ultrasonic beam was realized from the GHz FZP microfluidicactuator.

A metal washer/cylinder was adhesively attached on the receivetransducer side such that the receive transducer was centered within thewasher. The inner diameter of the cylinder was 3.25 mm and the heightwas 0.8 mm. This formed a fluid capacity of 6.6 μl. The well formed bythe cylinder was filled with a mixture of deionized water, polystyrene(PS) microspheres of 2 μm diameter, and soap solution for reducingsurface tension between spheres and water. FIG. 27A shows the 3D modelof the microfluidic actuator with the well and liquid mixture.

FIG. 26 shows an example of a box plot of surface displacement at thepoint of focus with different applied voltages. Twenty data points areplotted for each voltage.

The test setup was slightly modified for the microfluidic experiments;the input to the DUT came from the same VSG, but the DUT was now placedunder a Keyence VW-9000 high speed microscope. Upon application of aninput signal from the VSG to the transmit transducer, streaming vorticesaround the receive transducer, or the region of focus was observed. FIG.27C shows an example of an image of the streaming patterns observedaround the region of focus.

The amplitude of the input signal was varied from 1-5V, and the videosof the micro particle streaming movements were recorded. From thesevideos, the streaming velocity of the particles were estimated. Thequadratic behavior of streaming velocity with applied voltage is shownin FIG. 28. Average streaming velocity of about 2636 μm/s was observedfor an applied voltage of 5V. Such high streaming velocities wereobserved because of the enhanced radiation and streaming forces arisingdue to GHz frequency acoustic waves, and highly localized microbeam fromthe Fresnel lens configuration.

Described above is a GHz ultrasonic microfluidic actuator is presented.The device employs a thickness mode AlN piezoelectric transducer stack,which is in principle CMOS compatible. The thickness mode resonance ofthe FZP transducer generates bulk waves into the silicon substrate thatfocus constructively at the intended focal point, which is on theopposite side of the wafer. Although a smaller receive transducer wasused here to measure the received signals electrically, the receivetransducer is not required for microfluidic actuation. The focusedultrasonic wave displaces the silicon dioxide surface on the receiveside which then propagates through the fluid.

Owing to high dissipation of the GHz ultrasonic field in water, a strongacoustic streaming force is generated; which pushes the fluid out andrecirculates forming spherical vortex shell around the focal point. Thehighly defined focal point is an opportunity to create microfluidicsystems with distributed fluidic sources controlled from the transmittransducer side.

FIG. 27A shows an example of a 3D sketch of the microparticle actuatorassembly. FIG. 27B shows an example of a cross sectional sketch showingthe streaming vortices in liquid around the receive transducer. FIG. 27Cshows an example of a streaming patterns observed around the circulartransducer in the receive side.

FIG. 28 shows an example of a box plot of streaming velocity versusapplied voltage. Ten data points are plotted for each voltage.

The ability to change the frequency of the ultrasound and amplitude canalso be used to spread the spatial extent of the force and itsamplitude. Since the voltages required are CMOS compatible, and thefabrication process is also CMOS compatible, microfluidic samples placedon the receive side of the silicon die can be enabled easily with theultrasonic actuator presented here. Further work is required toinvestigate the effect of microfluidic channel boundary conditions tocontain the field and generate flow in channels.

In summary, a GHz actuator was designed, fabricated and tested formicroparticle actuation. This can find applications in microparticlecapturing, and biological assays requiring localized mixing and pumping.The device when integrated with CMOS can not only reduce the size andcost of the test setting drastically, but also enable digital controland automation of particle manipulation in a closed lab-on-chipenvironment.

While this document contains many specifics, these should not beconstrued as limitations on the scope of an invention that is claimed orof what may be claimed, but rather as descriptions of features specificto particular embodiments. Certain features that are described in thisdocument in the context of separate embodiments can also be implementedin combination in a single embodiment. Conversely, various features thatare described in the context of a single embodiment can also beimplemented in multiple embodiments separately or in any suitablesub-combination. Moreover, although features may be described above asacting in certain combinations and even initially claimed as such, oneor more features from a claimed combination can in some cases be excisedfrom the combination, and the claimed combination may be directed to asub-combination or a variation of a sub-combination. Similarly, whileoperations are depicted in the drawings in a particular order, thisshould not be understood as requiring that such operations be performedin the particular order shown or in sequential order, or that allillustrated operations be performed, to achieve desirable results.

Only a few examples and implementations are disclosed. Variations,modifications, and enhancements to the described examples andimplementations and other implementations can be made based on what isdisclosed.

Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. Moreover, the separation of various system components in theembodiments described in this patent document should not be understoodas requiring such separation in all embodiments.

What is claimed is:
 1. An ultrasonic microfluidic flow control device, comprising: an array of ultrasonic transducers arranged on a first side of a complementary metal oxide semiconductor (CMOS) substrate, wherein the array of ultrasonic transducers is configured to direct ultrasonic energy into a microfluidic channel, and wherein the microfluidic channel is structured on a second side of the CMOS substrate; one or more driver circuits arranged on the first side of the CMOS substrate, wherein each ultrasonic transducer is operatively associated with one of the one or more driver circuits, wherein each ultrasonic transducer is driven by a driver signal from the associated driver circuit, and wherein each ultrasonic transducer is configured to produce ultrasound in response to an electrical driving signal at a frequency above 100 MHz; and one or more electrical contacts associated with each ultrasonic transducer in the array of ultrasonic transducers, wherein the one or more electrical contacts associated with each ultrasonic transducer is configured to apply the driver signal from the associated driver circuit.
 2. The ultrasonic microfluidic flow control device of claim 1, wherein each driver signal has a predetermined phase and amplitude or a predetermined duty cycle to cause pumping of a liquid in the microfluidic channel.
 3. The ultrasonic microfluidic flow control device of claim 1, wherein each driver signal has a predetermined phase and amplitude or a predetermined duty cycle to cause the ultrasonic microfluidic flow control device to operate as a valve by allowing fluid to flow with low fluidic resistance in the microfluidic channel when the each driver signal is off and preventing fluid from flowing with high fluidic resistance when each driver signal is on.
 4. The ultrasonic microfluidic flow control device of claim 1, wherein each driver signal has a predetermined phase and amplitude or a predetermined duty cycle to cause mixing of a liquid in the microfluidic channel.
 5. The ultrasonic microfluidic flow control device of claim 1, wherein each of the array of ultrasonic transducers produces an ultrasound signal focused on the microfluidic channel.
 6. The ultrasonic microfluidic flow control device of claim 1, wherein the ultrasonic microfluidic control device causes a microfluidic particle in the microfluidic channel to flow in the microfluidic channel.
 7. The ultrasonic microfluidic flow control device of claim 1, wherein the array of ultrasonic transducers is a one-dimensional array.
 8. The ultrasonic microfluidic flow control device of claim 7, wherein array of ultrasonic transducers is arranged as a 1×4 array.
 9. The ultrasonic microfluidic flow control device of claim 1, wherein the array of ultrasonic transducers is a two-dimensional array.
 10. The ultrasonic microfluidic flow control device of claim 1, wherein each ultrasonic transducer in the array of ultrasonic transducers occupies an area that is 40μ×40μ or 50μ×50μ with a gap between the ultrasonic transducers in the array of ultrasonic transducers of between 2μ and 50μ.
 11. The ultrasonic microfluidic flow control device of claim 1, wherein each of the array of ultrasonic transducers responds to electrical signals at a frequency between 100 MHz and 10 GHz.
 12. The ultrasonic microfluidic flow control device of claim 1, wherein each ultrasonic transducer in the array of ultrasonic transducers is a Fresnel type transducer.
 13. The ultrasonic microfluidic flow control device of claim 1, wherein each ultrasonic transducer in the array of ultrasonic transducers is structured to cause ultrasound from each ultrasonic transducer to be focused at a predetermined point, and wherein the ultrasound from each ultrasonic transducer in the array of ultrasonic transducers is structured to constructively add in an ultrasonic amplitude or add in an ultrasonic power.
 14. A method of microfluidic flow control, comprising: focusing ultrasonic energy, from one or more ultrasonic transducers in an array of ultrasonic transducers, onto a microfluidic channel, wherein each ultrasonic transducer is configured to produce ultrasound in response to an electrical driving signal at a frequency above 100 MHz; and driving each of the one or more ultrasonic transducer in the array of ultrasonic transducers by a different driver circuit to cause a change in microfluidic flow in a channel according to a valve, a pump, or a mixer.
 15. The method of microfluidic flow control of claim 14, wherein each ultrasonic transducer in the array of ultrasonic transducers occupies an area that is 40μ×40μ or 50μ×50μ with a gap between the ultrasonic transducers in the array of ultrasonic transducers of between 2μ and 50μ.
 16. The method of microfluidic flow control of claim 14, wherein each of the one or more ultrasonic transducers responds to electrical signals at a frequency between 100 MHz and 10 GHz.
 17. The method of microfluidic flow control of claim 14, wherein each of the one or more ultrasonic transducer is a Fresnel type transducer.
 18. The method of microfluidic flow control of claim 16, wherein each ultrasonic transducer in the array of ultrasonic transducers is structured to cause ultrasound from each ultrasonic transducer to be focused at a predetermined point, and wherein the ultrasound from each ultrasonic transducer in the array of ultrasonic transducers is structured to constructively add in an ultrasonic amplitude or add in an ultrasonic power.
 19. A method of producing a microfluidic flow control device, comprising: fabricating an array of ultrasonic transducers on a first side of a complementary metal oxide semiconductor (CMOS) substrate; fabricating a microfluidic channel on the first side of the CMOS substrate, wherein the array of ultrasonic transducers is configured to direct ultrasonic energy into the microfluidic channel; fabricating one or more driver circuits arranged on a second side of the CMOS substrate, wherein each ultrasonic transducer is associated with one of the one or more driver circuits, wherein each ultrasonic transducer is configured to produce ultrasound in response to an electrical driving signal at a frequency above 100 MHz; and patterning one or more electrical contacts associated with each ultrasonic transducer in the array of ultrasonic transducers, wherein the one or more electrical contacts associated with each ultrasonic transducer is configured to apply a driver signal from an associated driver circuit.
 20. The method of producing a microfluidic flow control device of claim 19, wherein each ultrasonic transducer in the array of ultrasonic transducers is configured to respond to the electrical driving signal at a frequency between 100 MHz and 10 GHz.
 21. The method of producing a microfluidic flow control device of claim 19, wherein each ultrasonic transducer in the array of the ultrasonic transducers is a Fresnel type transducer. 